Enterprise Stent-assisted Cerebral Aneurysm Coiling: Can Antiplatelet Therapy be Terminated after Neointima Formation with the Enterprise Stent?

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1 Journal of Neuroendovascular Therapy 2016; 10: Online September 9, 2016 DOI: /jnet.oa Enterprise Stent-assisted Cerebral Aneurysm Coiling: Can Antiplatelet Therapy be Terminated after Neointima Formation with the Enterprise Stent? Katsutoshi Takayama, 1 Toshiaki Taoka, 2 Kaoru Myouchin, 1 Takeshi Wada, 2 Hiroyuki Nakagawa, 2 Ichiro Nakagawa, 3 Toshiteru Miyasaka, 2 Masahiko Sakamoto, 2 Shinichiro Kurokawa, 4 and Kimihiko Kichikawa 2 Objective: Patients who undergo Enterprise stent (ES)-assisted cerebral aneurysm coiling require long-term antiplatelet therapy (AT). Some studies have reported that cessation or modification of AT increases the risk of cerebral infarction. The aim of this study was to evaluate whether AT can terminated without increasing the risk of ischemic events among patients who have undergone ES-assisted cerebral aneurysm coiling. Methods: This study evaluated 9 with 11 unruptured aneurysms were confirmed to have neointima formation with the ES on follow-up angiography. Dual AT was given for 3 months postoperatively, then one antiplatelet agent was administered until 6 months postoperatively before termination of all AT. Incidences of ipsilateral ischemic events and stent occlusion after AT termination were assessed prospectively. Results: During follow-up (mean, 32.8 months; range, months) ipsilateral ischemic events and stent occlusion did not occur in any cases. Conclusion: Termination of AT 6 months postoperatively did not result in ischemic events among patients with neointima formation after ES-assisted cerebral aneurysm coiling. Keywords enterprise stent, antiplatelet therapy, cerebral aneurysm, coiling Introduction Patients who undergo Enterprise stent (ES)-assisted cerebral aneurysm coiling require long-term antiplatelet therapy (AT), but there are no definitive data to guide the duration of such therapy. Many groups of investigators have described using a 1 to 6-month period of dual AT with 1 Department of Radiology and Interventional Neuroradiology, Ishinkai Yao General Hospital, Osaka, Japan 2 Department of Radiology, Nara Medical University, Kashihara, Nara, Japan 3 Department of Neurosurgery, Nara Medical University, Kashihara, Nara, Japan 4 Department of Neurosurgery, Ishinkai Yao General Hospital, Osaka, Japan Received: April 8, 2016; Accepted: July 11, 2016 Corresponding author: Katsutoshi Takayama. Department of Radiology and Interventional Neuroradiology, Ishinkai Yao General Hospital, 1-41 Numa Yao, Osaka, , Japan takayamaneuroivs@par.odn.ne.jp 2016 The Editorial Committee of Journal of Neuroendovascular Therapy. All rights reserved. acetylsalicylic acid (ASA) ( mg) and clopidogrel (75 mg), followed by lifelong ASA therapy in patients who have undergone coiling with ES. 1 4) However, some of these patients require suspension of AT if the need for surgery or biopsy arises, and some studies have reported that delayed infarction can occur after cessation or modification of AT in patients who have undergone coiling with ES. 5 7) Conversely, long-term AT therapy is associated with a significant risk of hemorrhagic complications. 8,9) Therefore, the aim of our study was to evaluate whether AT could be terminated without increasing the risk of ischemic events among patients who have undergone ES-assisted cerebral aneurysm coiling. Materials and Methods Between July 2010 and July 2014, 9 patients with 11 unruptured aneurysms (four women; mean age, 65.8 years) were evaluated from among 40 consecutive patients who underwent ES-assisted cerebral aneurysm coiling. Treatment of unruptured aneurysms in our center is performed 201

2 Takayama K, et al. after careful assessment of perceived risk factors for rupture 10,11) and consultation with our multidisciplinary cerebrovascular team and the patient. Inclusion criteria for ES-assisted cerebral aneurysm coiling were as follows: (1) wide-neck saccular aneurysm, defined as aneurysm with a neck dimension 4 mm or a dome-to-neck ratio <2; (2) parent vessel diameter 4 mm; (3) morphology or size of the aneurysm considered to indicate difficulty of treatment using balloon remodeling techniques. The aneurysms were located as follows: poster communicating artery, n = 4; ophthalmic artery, n = 4; anterior choroidal artery, n = 2; cavernous internal carotid artery, n = 1. ESs were placed in patients without carotid siphon involvement in all cases of internal carotid artery aneurysm. The length of ES was as follows: 14 mm, n = 6; 22 mm, n = 5. The mean aneurysm size was 6.7 mm ( mm). All aneurysms were saccular aneurysm. Two aneurysms were recurrent aneurysms after prior coiling, and two aneurysms were recurrent aneurysms after post-coating. Patient demographics and aneurysm information are provided in Table 1. All patients with cerebrovascular or cardiovascular disease requiring AT or with a high risk of incomplete stent apposition located in an acute angle structure (e.g., carotid siphon) or within a small diameter parent artery were excluded. Follow-up angiography was performed at least 3 months after coiling in all patients, and neointima formation of ES confirmed angiographically. Neointima formation of ES was defined as present when the struts of the ES were angiographically embedded in multiple projections, except at the neck of the coiled aneurysm (Fig. 1D and 1E). Digital subtraction angiography (DSA) studies were performed on a twin, flat-panel angiographic system (AXIOM Artis dba; Siemens AG, Erlangen, Germany, or BRANSIST Safire DAR-9400f; Shimadzu Corporation, Kyoto, Japan) with a matrix. Selective catheterization of the vessel harboring the aneurysm was performed. All treatment procedure and follow-up angiography were performed by two interventional neuroradiologists have experienced at least over three hundreds coiling cases. The angiographic and MRA findings were evaluated by two senior neuroradiologists, and clinical data evaluated by senior neurosurgeon. DSA were obtained in multiple views to confirm neointima formation of ES. Dual AT (ASA 100 mg and clopidogrel 75 mg) was given until at least 3 months postoperatively, and after angiographic confirmation of the stent apposition, then one antiplatelet agent was given until at least 6 months postoperatively before termination of all AT. The incidence of ipsilateral ischemic events (transit ischemic attack, ischemic stroke) after termination of AT and the incidence of stent occlusion (as determined by contrast-enhanced magnetic resonance angiography (CE-MRA) at least 1 month after termination of AT) was prospectively assessed. All patients were obtained by informed consent. This study also was approved by our institutional review board. Results In all patients, AT terminated at a mean time point of 9.7 months (range, 6 14 months). Two patients terminated AT at 6 months (Fig. 1), two patients terminated AT at 7 months, three patients terminated AT at 12 months, and two patients terminated AT at 14 months. During follow-up (mean, 32.8 months; range, months), no ipsilateral ischemic events or stent occlusion occurred in any of the cases. All patients underwent follow-up (mean, 8.0 months; range, months) evaluation via CE-MRA or DSA. All aneurysms were completely occluded, and no in-stent stenosis was observed. After termination of AT, one patient underwent follow-up for 1 month, one patient underwent follow-up for 2 months, three patients underwent follow-up for 6 months, one patient underwent follow-up for 12 months, and three patients underwent follow-up for over 12 months. Discussion Several groups of investigators have utilized the following AT regimen after ES-assisted cerebral aneurysm coiling: ASA ( mg) and clopidogrel (75 mg) for a minimum of 1 6 months, followed by lifelong therapy with ASA alone, 1 4) and some studies have reported that ischemic events can occur if AT therapy is modified or terminated. For example, Mocco et al. 5) reported that delayed thrombotic events occurred in 7 of 213 (3%) patients after ESassisted coiling in whom dual AT therapy was terminated. In a similar context, Lee et al. 6) reported that delayed infarction occurred in 11 of 261 (4.2%). Further, Rossen et al. 12) reported that discontinuation of clopidogrel therapy was associated with a 5% risk of ischemic events in patients who have undergone treatment with stent techniques. These reports suggest that some patients who have undergone ES-assisted procedures require lifelong dual AT therapy. Some patients require temporary cessation of AT for surgery or biopsy, or permanent cessation of AT due to hemorrhagic complications. Indeed, the risk of major hemorrhage with dual AT is 2.1% per year as compared with 1.1% per year for aspirin alone among patients with 202

3 Enterprise Stent-assisted Cerebral Aneurysm Coiling Table 1 Patient demographics and aneurysm information Case Age (years)/ gender Aneurysm location Maximum diameter of aneurysm (mm) Shape of aneurysm Presentation/ indication for treatment Stent length Follow-up angiographic result Months of antiplatelet therapy Months of follow-up CE-MRA or angiography after AT termination 1 84/F IC-Pcom.A 14.0 Saccular Incidental 22 mm CO /F Cavernous IC 7.2 Saccular Incidental 14 mm CO /F Oph. 3.6 Saccular Incidental 28 mm CO /F IC-Pcom.A 8.7 Saccular Incidental 14 mm CO /F Oph. 8.7 Saccular Incidental 14 mm CO /F Oph. 9.4 Saccular Incidental 14 mm CO /M Oph. 5.0 Saccular Incidental 14 mm CO /M 9 55/F IC-Ach.A 3.6 Saccular IC-Pcom.A 2.7 Saccular IC-Ach.A 4.0 Saccular IC-Pcom.A 6.3 Saccular Regrowth after coating Regrowth after coating Recurrence post coiling Recurrence post coiling 22 mm 22 mm CO 14 CO 14 CO 12 CO Ach.A: anterior choroidal artery; AT: antiplatelet therapy; CE-MRA: contrast enhanced MRA; CO: complete occlusion; F: female; IC: internal carotid artery; M: male; Oph: ophthalmic artery; Pcom.A: posterior communicating artery 203

4 Takayama K, et al. A B C D E F Fig. 1 Coil embolization with the Enterprise stent (ES) for a left ophthalmic artery aneurysm. (A) Left carotid angiogram shows (right anterior oblique view) the ophthalmic artery aneurysm (arrow). (B) Left carotid angiogram immediately after coil embolization with ES shows complete occlusion of the aneurysm (arrow). Arrowheads indicate tantalum markers at either end of the ES. (C) Unsubtracted image. Arrowheads indicate tantalum markers at either end of the ES. (D) Follow-up angiogram at 3 months after coil embolization with ES. (E) Unsubtracted image. Left carotid angiogram (right anterior oblique view) demonstrates complete occlusion of the aneurysm (arrow), and the ES is embedded (arrowheads). (F) Contrast-enhanced magnetic resonance angiography at 6 months after the termination of antiplatelet therapy shows good patency of the parent artery (arrows). recent lacunar strokes. 8) Further, even ASA monotherapy is associated with the occurrence of gastric ulcer. Sostres et al. 9) reported that the estimated average excess risk of symptomatic gastric ulcer related to low-dose ASA was five cases per 1000 ASA users per year. These data suggest that the ability to safely terminate AT would be of benefit. Incomplete stent apposition is associated with delayed ischemic events and the need for lifelong AT. Hellar et al. 13) reported that incomplete stent apposition of ES is associated with delayed ischemic events despite AT. Delayed ischemic events occurred in 8 (16%) of 50 cases, and all cases involved patients with incomplete stent apposition. In patients undergoing drug-eluting stent placement for coronary artery disease, several studies 14,15) suggested that delayed arterial healing and stent malapposition may be important causes of very late stent thrombosis (thrombosis at >1 year after stent deployment). Heller et al. 16) evaluated for incomplete stent apposition using high-resolution flat-panel computed tomography (CT). Kinking or wall apposition of ES before coiling was detected by diluted contrast-enhanced high-resolution flat-panel CT more often than by DSA. However, depending on aneurysm volume, flat-panel CT may be difficult after ES and coiling because of metal artifact or coil mass. Therefore, we did not evaluate neointima formation of ES by high-resolution flat-panel CT. Although neointima formation of ES was evaluated by DSA in our study, we could not evaluate whether there was neointima formation in the aneurysm neck. Therefore, the development of new technology to evaluate for neointima formation of ES would be of benefit. Heller et al. 16) reported that incomplete stent apposition of ES was associated with stent-subtended arc angle or parent vessel diameter. In our study, patients with a high risk of incomplete stent apposition located in an acute angle structure (e.g., carotid siphon) or within a small diameter parent artery were excluded, because incomplete stent apposition and delayed arterial healing was associated with delayed ischemic 204

5 Enterprise Stent-assisted Cerebral Aneurysm Coiling events and late stent thrombosis. Neointima formation within the ES was confirmed by DSA in all cases in which stent apposition was complete, which may account for the absence of delayed ischemic event and late stent thrombosis despite termination of AT. These results suggest that neointima formation within the ES is an important criterion for termination of AT without increasing the risk of ischemic events. In our study, stent occlusion was evaluated by CE-MRA or DSA, because it is difficult to evaluate the patency of artery on time-of-flight MRA due to susceptibility artifact from the ES. 17) In current study, there was no stent occlusion and no recurrence of aneurysm in all 10 patients who underwent follow-up with CE-MRA. Limitations of this study included the fact that it was conducted within a single center and that it was a nonrandomized study with a small sample size. Further, posterior circulation or anterior cerebral artery and middle cerebral artery aneurysms with a small diameter parent artery aneurysm were not included in this study. Therefore, a multicenter prospective study is required to validate these results. In conclusion, termination of AT at least 6 months postoperatively did not result in ischemic events among patients with neointima formation after ES-assisted cerebral aneurysm coiling. Neointima formation of ES may be a criterion for termination of AT without increasing the risk of ischemic event, and therefore, avoidance of incomplete stent apposition is indicated. Disclosure Statement We declare that we have no conflict of interest. References 1) Weber W, Bendszus M, Kis B, et al: A new self-expanding nitinol stent (Enterprise) for the treatment of wide-necked intracranial aneurysms: initial clinical and angiographic results in 31 aneurysms. Neuroradiology 2007; 49: ) Peluso JP, van Rooij WJ, Sluzewski M, et al: A new selfexpandable nitinol stent for the treatment of wide-neck aneurysms: initial clinical experience. AJNR Am J Neuroradiol 2008; 29: ) Siddiqui MA, J Bhattacharya J, Lindsay KW, et al: Horizontal stent-assisted coil embolisation of wide-necked intracranial aneurysms with the Enterprise stent a case series with early angiographic follow-up. Neuroradiology 2009; 51: ) Wakhloo AK, Linfante I, Silva CF, et al: Closed-cell stent for coil embolization of intracranial aneurysms: clinical and angiographic results. AJNR Am J Neuroradiol 2012; 33: ) Mocco J, Fargen KM, Albuquerque FC, et al: Delayed thrombosis or stenosis following enterprise-assisted stent-coiling: is it safe? Midterm results of the interstate collaboration of enterprise stent coiling. Neurosurgery 2011; 69: ; discussion ) Lee SJ, Cho YD, Kang HS, et al: Coil embolization using the self-expandable closed-cell stent for intracranial saccular aneurysm: a single-center experience of 289 consecutive aneurysms. Clin Radiol 2013; 68: ) Fargen KM, Hoh BL, Welch BG et al: Long-term results of enterprise stent-assisted coiling of cerebral aneurysms. Neurosurgery 2012; 71: ; discussion ) SPS3 Investigators, Benavente OR, Hart RG, et al: Effects of clopidogrel added to aspirin in patients with recent lacunar stroke. N Engl J Med 2012; 367: ) Sostres C, Gargallo CJ: Gastrointestinal lesions and complications of low-dose aspirin in the gastrointestinal tract. Best Pract Res Clin Gastroenterol 2012; 26: ) Chmayssani M, Rebeiz JG, Rebeiz TJ, et al: Relationship of growth to aneurysm rupture in asymptomatic aneurysms 7 mm: a systematic analysis of the literature. Neurosurgery 2011; 68: ; discussion ) Wiebers DO, Whisnant JP, Huston J, et al: Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment. Lancet 2003; 362: ) Rossen JD, Chalouhi N, Wassef SN, et al: Incidence of cerebral ischemic events after discontinuation of clopidogrel in patients with intracranial aneurysms treated with stentassisted techniques. J Neurosurg 2012; 117: ) Heller R, Calnan DR, Lanfranchi M, et al: Incomplete stent apposition in Enterprise stent-mediated coiling of aneurysms: persistence over time and risk of delayed ischemic events. J Neurosurg 2013; 118: ) Cook S, Wenaweser P, Togni M, et al: Incomplete stent apposition and very late stent thrombosis after drug-eluting stent implantation. Circulation 2007; 115: ) Lee CW, Kang SJ, Park DW, et al: Intravascular ultrasound findings in patients with very late stent thrombosis after either drug-eluting or bare-metal stent implantation. J Am Coll Cardiol 2010; 55: ) Heller RS, Malek AM: Parent vessel size and curvature strongly influence risk of incomplete stent apposition in enterprise intracranial aneurysm stent coiling. AJNR Am J Neuroradiol 2011; 32: ) Takayama K, Taoka T, Nakagawa H, et al: Usefulness of contrast-enhanced magnetic resonance angiography for follow-up of coil embolization with the enterprise stent for cerebral aneurysms. J Comput Assist Tomogr 2011; 35: